About 12 million units of red blood cells are transfused annually in the United States. Patients who are acutely anemic may have bled from trauma, extensive laboratory testing, childbirth, gastrointestinal disease, or complex orthopedic, cardiac or transplant surgery. The indications for red cell transfusion are unclear because of lack of measurable endpoints that indicate inadequate tissue oxygen and/or function. Hemoglobin (Hb) concentration alone is insufficient as an indication. The goal of this project is to find endpoints that will measure tissue oxygenation and/or function in acute anemia. In the previous grant period, we used the acute isovolemic hemodilution model and found no changes in subcutaneous tissue oxygen and infrequent ECG ST changes at Hb concentration of 5 g/dL. Importantly, we found cognitive function impairment at Hb concentrations of 5-6g/dL that was reversible with transfusion of fresh red blood cells. We now propose to continue to use the acute isovolemic hemodilution model to study the efficacy of therapy for this anemia- associated cognitive impairment, to further study the effect of anemia on the nervous system and the heart, and to study subcutaneous tissue oxygen in surgery patients. The specific aims are to determine whether: (1) transfusion of stored rather than fresh red cells, or (2) 100% inspired oxygen will reverse the anemia-associated cognitive impairment; in the nervous system during acute anemia, whether (3) cerebral blood flow distribution is changed, (4) evoked potentials are impaired and (5) cerebral information processing slowing occurs. In addition, we will determine whether (6) heart rate is associated with myocardial ST changes in acute anemia, and whether (7) subcutaneous tissue oxygen is reduced in acutely anemic surgical patients. Data from this research will provide new information as to how acute anemia impairs neurological, cardiac and subcutaneous oxygenation and/or function and which treatment modalities are effective. This research is directly responsive to one of the RFA's area of emphasis: "Indications for Red Blood Cell or Platelet Transfusion."